CN1238789A - Water-soluble polymers for reduction of dietary phosphate or oxalate absorption - Google Patents

Water-soluble polymers for reduction of dietary phosphate or oxalate absorption Download PDF

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CN1238789A
CN1238789A CN97199954A CN97199954A CN1238789A CN 1238789 A CN1238789 A CN 1238789A CN 97199954 A CN97199954 A CN 97199954A CN 97199954 A CN97199954 A CN 97199954A CN 1238789 A CN1238789 A CN 1238789A
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polymkeric substance
phosphate radical
oxalate
polyglycol
water
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J·西蒙
T·T·马斯特森
A·D·斯特里克兰
M·L·希尔顿
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Dow Global Technologies LLC
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Dow Chemical Co
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
    • C08G65/22—Cyclic ethers having at least one atom other than carbon and hydrogen outside the ring
    • C08G65/223—Cyclic ethers having at least one atom other than carbon and hydrogen outside the ring containing halogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/04—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers only
    • C08G65/22—Cyclic ethers having at least one atom other than carbon and hydrogen outside the ring
    • C08G65/24—Epihalohydrins

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polyethers (AREA)
  • Medicinal Preparation (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)

Abstract

The present invention is directed to a water-soluble polyether glycol polymer having: a structural backbone of carbon atoms and oxygen atoms where there are at least two consecutive carbon atoms present between each oxygen atom; a moiety on the backbone of the polymer or a functionalized derivative on the polymer, that is cationic at physiological pH and permits complexation with phosphate or oxalate; and an average molecular weight from about 5,000 to about 750,000 Daltons. These polymers are formulated for oral dosage to reduce the phosphonate or oxalate levels in an animal. The process of preparing these polymers and the method of reducing gastrointestinal absorption of phosphate and oxalate are included.

Description

Be used for reducing the water-soluble polymers of diet phosphate radical or oxalate absorption
Invention field
The present invention relates to contain can with the composition of phosphate radical or oxalate coordinate water-soluble polymers, the preparation method of polymkeric substance, polymkeric substance is used in animal body carrying out coordination preventing the using method of gastro-intestinal system to its absorption with diet phosphate radical or oxalate, and they are as the prescription of non-internal-absorting preparation.
Background of invention and general introduction
Just have bad effect after the content overrun of existing known phosphoric acid serum.Hyperphosphatemia, be the symptom that contains excess phosphoric acid salt in the serum, be found the illness that can cause (for example, referring to M.E.Rubin etc. as osteodystrophy and secondary hyperphosphatemia, Archives of Internal Medicine (Arch.Intern.Med.) 124,663-669 (1969); With E.Slatopolsky etc., international kidney magazine (Kidney Int ' l.) 2,147-151 (1972)).The patient that great majority show the renal failure symptom has the danger of suffering from hyperphosphatemia.Hyperphosphatemia will take place in the time spent of doing that no longer has been enough to drain the phosphate radical in the diet of eating when kidney, and cause many complication (for example, referring to D.Mizumoto etc., Clin.Nephrol.42,315-321 (1994), this article has detailed description to clinical course).
Treatment to long-term renal failure patient needs very high cost and takies a large amount of medical time.That renal failure patient can't drain in their diet to be absorbed but be not the needed all liquid of health, sodium salt, sylvite, muriate, phosphate radical, nitrogen and other mineral substance.Little of a small amount of dietary restrictions to these patients' treatment, big to strict dietary restrictions, when kidney shape attitude worsens even will carry out peritoneal dialysis or hemodialysis is analysed.Many patients may need renal transplantation, but owing to lack suitable donation kidney device, the hemodialysis that patient may need to carry out for many years before transplanting realizes is analysed.According to medical statistics, nearly 150,000 patients of the U.S. accept hemodialysis and analyse treatment at present.When renal failure needed dialysis treatment, the disorder of many metabolic aspects can appear usually.Because kidney is no longer handled the liquid that is absorbed and the ionogen that originally need drain, the level of sodium salt, sylvite, calcium salt, phosphate radical, muriate, water and various trace elements often will be higher than normal range in the whole health.Retain excessive liquid in the body and produce unusual hormone and can cause hypertension.Pathobolism can cause hyperlipidaemia and hypercholesterolemia disease.Therefore, the patient who carries out kidney dialysis often needs a large amount of treatments to control the chemical constitution of what and serum of their blood pressure, hormone situation, fat.They also must carry out strict going on a diet usually, comprise minimum absorption albumen, and accurate liquid limits, strict sodium salt restriction, lower fat taken in and the simple carbohydrate of high absorption.The restriction of these diet aspects is necessary, because the kidney dialysis can not make intravital chemical constitution and consequent hormonal readiness return to normal scope effectively.Even in order to remove liquid, urea, Creatinine and the ionogen that is produced in the state lower body of going on a diet, patient often needs to dialyse weekly 2 to 4 times, needs 4 to 8 hours at every turn.Adopt the method for dialysis to be difficult to control phosphate radical especially, because common used filter membrane is little to the Dialysis of phosphate radical in the dialysis.
Except that renal failure, other disease also can cause hyperphosphatemia.Elementary parathyroid gland hypofunction disease is a unusual etiology causing hyperphosphatemia (for example, referring to D.Mizumoto etc., Clin.Nephrol, 42,315-321 (1994)).Phosphate radical is poisoned and also can be caused by the enema of having taken phosphorous acid group, oral purgative or urinary acidifier.Thyroid carcinoma often causes hyperphosphatemia.Go fast also may cause hyperphosphatemia in the knurl process at amic therapy method, also may jeopardize kidney (for example, referring to T.Smith, South.Med.J.81,415-416 (1988)) simultaneously owing to remove in the knurl to produce excessive uric acid.The baby that mother suffers from diabetes also be in the news and find that hyperphosphatemia is arranged (for example, referring to R.C.Tsang etc., paediatrics magazine (J.Pediatics), 89,115-119 (1976)).Though common like that not as renal failure, these diseases also can cause serious health problem.The method for the treatment of the cause of disease of these hyperphosphatemias comprises from diet controls the absorption of phosphate radical to reduce the absorbed dose of phosphate radical.
The another kind of disease that causes serious health problem and high cost is the formation of urinary stone disease.Have 400,000 cases because of the urinary stone disease hospital care every year in the North America.It is oxalate calculus that 234,000 examples are arranged in these cases.Some mammiferous metabolic pathway can cause the formation of oxalate, and oxalate can not must excrete by kidney further by metabolism.But, the oxalate that these approach produced accounts for less than 1/3rd of urine medium-height grass acid group, the oxalate of diet picked-up then accounts for 67% (for example, referring to R.P.Holmes etc., Scanning Microsco.9:1109-1120 (1995)) of metabolic disease patient urine mesoxalic acid root origin.The oxalate with the diet picked-up that forms in the body all must excrete by kidney with other material such as calcium, excessive hydrogen, urea and sodium.Caoxalate and the oxalic acid solubleness in urine is low, precipitates easily and forms urinary stone disease.Suffer from steatorrhea, ileal resection, ileum bypass, serious ileal mucous membrane disease or the insufficient patient of pancreas function and edible oxalate is had higher absorption than healthy people, and easilier (for example suffers from the oxalate calculosis, referring to J.Q.Stauffer, U.S.'s digestive ailment magazine (Am.J.Dig.Dis.), 22:921-928 (1977); A.F.Hofmann etc., international woman produce magazine (Int.J.Obes.) 5:513-518 (1981); K.Dharmsathaphorn etc., digestive ailment science (Dig.Dis.Sci.) 27:401-405 (1982); Gastroenterology 84:293-300 (1983); And D.P.D ' Cruz etc., Britain's urology magazine (Br.J.Urol.) 64:231-234 (1989)).Genetic hyperoxaluria causes the formation of oxalate in the body, and the latter causes the formation of kidney oxalate calculus.Diet is taken in oxalate can aggravate the formation of these patient's urinary stone diseases.
Though at present the amount of the diet absorption of phosphorus restriction acid group with phosphate radical in the reduction body emphasized in the treatment of hyperphosphatemia, this often is not enough to treat fully hyperphosphatemia and is very bothersome for the patient.Except that dietary restriction, be necessary often to carry out treatment means that some phosphate radicals that prevent to be digested are absorbed by gastro-intestinal system (for example, referring to J.A.Ramirez etc., international kidney magazine 30,753-759 (1986); With M.S.Sheikh etc., Journal of Clinical Investigation (J.Clin.Invest.) 83,66-73 (1989)).Similarly, the treatment of hyperoxaluria or concentrate on by getting rid of various diet is taken in the diet that reduces oxalate, or concentrates on the absorption to oxalate that prevents gastro-intestinal system.Dietary restriction is a difficulty and chaotic.Some article authors advise getting rid of all green vegetables, Rheum plant, tea and chocolate.Though other articles author allows edible green vegetables except that spinach, advise to be limited in and add beet, nut, wheat bran and strawberry (for example, referring to L.K.Massey etc., J.Am.Diet.Assoc.93:901-906 (1993)) in the diet.Some article author advises taking in the calcium of a large amount, and some author then requires to limit the absorption of calcium.Some author requires low protein diet, and some author insists that then albumen is irrelevant to treating, and must be reduced to minimum to eating of carbohydrate and fat.The enteron aisle wedding agent of the oxalate that suggestion is adopted has comprised calcium, magnesium, aluminium and fiber (for example, referring to R.P.Holmes etc., Scanning Microsco.9:1109-1120 (1995) and A.F.Hofmann etc., international woman produces magazine 5:513-518 (1981)).Other authors worry that excessive calcium can cause the formation of more calculus.Some author opposes to adopt fiber.These means nones are effective especially, verified have in after removing urinary stone disease first 6 years of 50% patient suffer from urinary stone disease again.Preferred methods of treatment should comprise adopting and a kind ofly combines to prevent the preparation of its absorption with oxalate in gastro-intestinal system.Usually realization and phosphate radical or oxalate bonded method comprise the employing coordination agent.
" coordination agent " is the compound that attracts other specific compound and they and coordination agent are combined.Can target molecule or ion be attracted mutually with coordination agent by many different mechanism.Simple coordination agent can be and to generate the ion that sedimentary insoluble compound takes place subsequently with a kind of substance reaction.The reaction that two kinds of ions generate insoluble molecule is one of the simplest mode of forming of title complex.
" sequestrant " is a kind of of coordination agent, can form the title complex that is called " inner complex ".Sequestrant forms two or more coordinate-covalent bonds by at least two sites in the coordination agent and other compound, ion or atom.Therefore these sites when the atom that is engaged or molecule link to each other with the two ends covalent linkage of sequestrant, can form and contain 4 to 10 or more polyatomic ring usually on " arm " that contain 3 to 8 atoms.Part is because the formation of this ring structure, inner complex than generating by same two molecules but the compound that only forms a coordinate-covalent bond to more stablize.When several " arms " worked the several ring of formation, the stability of inner complex also was improved.Except the number that increases ring improves the stability, these compounds also improve stability by the steric interaction between the dissimilar arm, and these arms are surrounded atom or the molecule that is engaged, thereby have prevented that they are easy to division with title complex.
The coordination agent of other form comprises that those pass through the ion sucking action and attract the also compound of binding molecule.It also can be that coordination agent attracts and in conjunction with the reactive force source of coordination compound that dipole-dipole or dipole-ionic attract.Other has and helps the reactive force that sequestrant works and comprise hydrophobic and the aqueous favoring mutual effect.
Above-mentioned these reactive forces that provide are as an illustration purely, are not to have comprised that coordination agent attracts and all reactive forces of binding compounds.
The solid resin of functionalization has been used to cooperate many biologically important materials.Courage steroid styrylamine (cholestyramine) for example, it is that a part of styrene monomer is by the crosslinked polystyrene of level Four ammonium muriate functionalization.This resin can attract and in conjunction with cholic acid, thus can prevent they by the absorption of gastro-intestinal system (referring to " QuestranTM Powder ", Bristol-Meyers Squibb, Physicians Desk Reference, the 51st edition, 1997, p774-776).But the shortcoming of courage steroid styrylamine is that gravel taste beastly is arranged, and its binding ability is low.This needs the patient to take heavy dose of solid that is difficult to swallow, and makes the patient be difficult to accept.In addition, courage steroid styrylamine displaces its chlorine atom with the cholic acid ionic bond time.When the dosage of courage steroid styrylamine also is lower than when curing the required dosage of patient, the chlorine dose of release often has been enough to cause the acidismus in the metabolism.Gravel taste beastly, low binding ability and from the resin unwanted a large amount of these problems of ionic ion-exchange are common issue with of present most of resins.
Concentrated on coordination agent treatment renal failure patient's hyperphosphatemia and to have adopted aluminium salt or calcium salt in gastro-intestinal system, to come the precipitate phosphoric acid root.Aluminium salt (is generally oxyhydroxide, for example the Amphojel of Wyeth-Ayerst company TMOr the Maalox of Ciba company TM) be proved to be and be not very good, because aluminium can be absorbed and cause osteomalacia or nervous system disease by gastro-intestinal system.Though the acetate (PhosLo of Braintree company TM), Citrate trianion and alginates also be applied, but the carbonate of the calcium (Tums of SmithKline Beecham company TM) be present most widely used clinically reagent.These reagent can cause the excessive absorption of calcium, cause the calcification of soft tissue.Recently, beta-hydroxy-Beta-methyl Calcium Butyrate is proposed the coordination agent (for example, referring to M.F.Sousa etc., Nephron.72,391-193 (1996)) as phosphate radical.This salt also works by generating calcium phosphate, causes the existing all problems of other calcium salt equally.This calcium salt is recommended, and mainly to be for the kidney dialysis patients because beta-hydroxy-Beta-methyl butyric acid is in the news be to improve proteinic metabolism.Someone compares anionite-exchange resin and aluminium salt external.Bio-Rex TM5, Dowex TMXF 43254, Dowex TMXY 40012 and Dowex TMXY 40013 has the aluminum compound binding ability of half approximately.Dowex TMSBR and Dowex TM1-X8 can be in conjunction with 1/3rd phosphate radical of aluminium salt institute binding capacity.Dowex TMXF 43311 and Dowex TMXY 40011 can (all Dowex resins be Dow chemical company and produce in conjunction with 80% phosphate radical of aluminium salt institute binding capacity, be based on the strong basic type anion-exchange resin of level Four ammonium functional group) (for example, referring to H.M.Burt etc., Uremia Invest.9 (1), 35-44 (1985-1986) and H.M.Burt etc., pharmacy science magazine (J.Pharm.Sci.) 76 (5), 379-383 (1987)).Because these reagent discharge the muriate that can cause acidismus, need heavy dose of its low binding ability that compensates, and can limit its safe level preventing in conjunction with cholic acid, thereby they are not applied to the patient as yet at present because of fat malabsorption causes dysentery disease.The somebody advises other phosphate radical coordination agent, (for example comprise molysite, crosslinked dextran iron, rare-earth salts and zirconyl chloride, referring to K.Spengler etc., Nephrol., Dial., Transplant.11,808-812 (1996) and L.Graff etc., Res.Commun.Mol.Pathol.Pharmacol.90,389-401 (1995)).Every kind is all come the complexing phosphate radical by form precipitation between metal and phosphate radical in these reagent.None has been used for volunteer or patient in these reagent.Seek phosphate radical coordination agent active quantity and just illustrating that people need better to treat the method for hyperphosphatemia to replace present method of going on a diet or known drug therapeutics.
The present invention's general introduction
Astoundingly, have now found that, can adopt a kind of water miscible polyether glycol polymkeric substance now with different as the water-insoluble resin and the polymkeric substance of phosphonate radical in the body or oxalate minimizing agent.This polymkeric substance has the structure main chain backbone of carbon atom and Sauerstoffatom, wherein has two successive carbon atoms between each Sauerstoffatom at least.The example of this base polymer comprises polyoxyethylene glycol and polypropylene glycol.These polymkeric substance must be water miscible and contain a kind of group or contain the deriveding group of functionalization in the main chain backbone of polymkeric substance in polymkeric substance, these groups under the physiological pH value for cationic and can carry out coordination with phosphate radical or oxalate.The molecular-weight average of these polymkeric substance is about 5000 to about 750000 dalton.These polymkeric substance are made formulation in a conventional manner and are used in the animal body to reduce the amount of phosphate radical or oxalate.For preparing this polymkeric substance, must pay close attention to that control obtains required molecular weight and solvability so that these polymkeric substance carry out functionalization through deriveding group commonly used.The detailed description of the invention
At first, the present invention relates to avoid the phosphate radical of release at present or a series of water soluble polyether glycol (PEG) of the existing problem of oxalate coordination agent.PEG comprises polyepihalohydrin (PEi) polymkeric substance, and wherein the part of the halogen in the PEi polymkeric substance can be chlorine, bromine or iodine.Polyether glycol (PEG) has the structure main chain backbone of carbon and oxygen, and wherein the number of successive carbon atom must be more than or equal to 2, and do not have the successive Sauerstoffatom.The example of polyether glycol has polyoxyethylene glycol and polypropylene glycol.These are generally the polyether glycol polymkeric substance of derivative form, it is water-soluble to make them (refer to homoiothermy type Mammals in animal body, comprise the people) form the homogeneous mixture with physiological liquid, rather than as existing known method, form the slurries of insoluble resin in physiological liquid.Have now found that this solvability can realize better mixing and promote the formation of title complex, can reduce the consumption of coordination agent like this.In addition, because this polyether glycol reagent do not have the gravel taste, and they more can reduce and may hide fully the taste of himself by the taste of the aqueous solution than resin, and therefore this reagent is easier is accepted by animal.
Can with PEG-D (polyether glycol derivative) polymkeric substance, particularly the ingredients of PEi-D polymer formation pharmaceutical formulation belongs to the ingredients of non-internal-absorting purposes.Therefore, to can be used for animal oral for these pharmaceutical formulations.The dosage of PEG-D polymkeric substance depend on the phosphate radical that must remove or the amount of oxalate.
Oral phosphate binder should be determined its consumption according to the ratio of binding site in the polymkeric substance and the phosphate radical in the diet.The phosphate radical that contains 48 to 65 mmoles in the diet of normal American every day.1 * dosage is meant that be 1 mole to every mole of diet phosphate radical polymkeric substance in conjunction with the mole number in site.5 * dosage is meant that be 5 moles to every mole of diet phosphate radical polymkeric substance in conjunction with the mole number in site.
The PEi/TMA (weight-average molecular weight Mw is 14000) that polymkeric substance has 5 * dosage is in the pH value is 7 times and salt solution, and every gram absorbs the phosphate radical of 0.69 mmole, combines about 98% phosphate radical.For absorbing the phosphate radical of 48 to 65 mmoles, should take this polymkeric substance of 70 to 94 grams every day.The PEi/EDA (weight-average molecular weight Mw is about 14000 to 20000) that polymkeric substance has 5 * dosage is in the pH value is 7 times and salt solution, every gram absorbs the phosphate radical (about 98% phosphate radical) of 1.38 to 1.73 mmoles, for absorbing all phosphate radicals in the diet, should take this polymkeric substance of 28 to 47 grams every day.
In the muroid test, 1 * dosage is very effective to reducing phosphoric acid serum in a week or two weeks.It is faster that 2 * dosage reduces the speed of phosphoric acid serum.5 * dosage can reduce phosphoric acid serum in several days, but mouse feed occurs unusually, and therefore the reduction of phosphate radical to a certain degree may cause owing to hungry.Can see from muroid test, though can in one day or two days, adopt up to 5 in order to reduce phosphate radical fast * dosage, daily dosage should be 0.5 * to 1 * dosage.Therefore, daily dosage should be every day about 3 to about 10 grams (or three meals in a day, every meal about 1 is to about 3 grams), and dosage in a short time can be as high as about 15 every day to about 50 grams (or three meals in a day, every meal about 5 is to about 15 grams).In order to remove the phosphate radical in the diet, the effective level of PEG-D or PEi-D is that every meal about 1 is to about 15 grams.
The intake of normal American's oxalate every day is 0 to 300 milligram and does not wait (0 to 3.3 mmole).Because the molecular weight of phosphate radical and oxalate is roughly the same, but roughly be 5% of phosphate radical amount in the amount of diet medium-height grass acid group, initial dose should be breakfast, lunch and dinner every day, and every meal about 0.6 is to about 2 grams.Therefore the effective level of PEG-D or PEi-D is that every meal about 0.6 is to about 2 grams.
Pharmaceutical formulation by PEG-D polymkeric substance of the present invention or PEi-D polymer manufacture can be any suitable oral property pharmaceutical formulation; the pharmaceutical formulation such as tablet, capsule, caplet, gelcaps, dry powder, dry granular mixture and other solid for mulation preparation that comprise solid form; with liquid such as suspensoid, solution and with can buy the fruit juice that obtains, the liquid mixture of having a dinner beverage and fruit beverage, but be not limited to this.Usually contain in the pharmaceutical formulation can be compatible with medicine carrier.Therefore in containing the pharmaceutical formulation of PEG-D, can contain in the following composition one or more: vehicle, wedding agent such as starch, Polyvinylpyrolidone (PVP) (PVP) and pregelatinized starch, lubricant such as Magnesium Stearate, calcium stearate and stearic acid, and other inert fraction, comprise that seasonings, sanitas, buffer reagent, anti-agglomerating agent, opacifying agent, sugar are as sucrose and synthetic sweetener, edible oil such as mineral oil and tinting material.Any edible pharmaceutical formulation general in food, beverage or medicine all can use as pharmaceutical formulation of the present invention by common mode.Final pharmaceutical formulation is prepared according to this professional known method.
For prevent phosphate radical or oxalate in gastro-intestinal system absorption and reduce side effect to stomach and intestine, should be preferably greater than about 10000 dalton greater than about 5000 dalton as PEG-D polymkeric substance or its molecular weight of PEi-D polymkeric substance of coordination agent.But the too high polymkeric substance of molecular weight may be with no longer soluble in water (referring to Finch, C.A., " chemical modification of water-soluble polymers and some crosslinking reaction ", the chemistry and technology of water-soluble polymers (Chemistry andTechnology of Water-Soluble Polymers), Finch, C.A. edit, Plenum, New York, NY, 1983, the 81-111 page or leaf .).The transformable scope of molecular weight depends on selected concrete PEG or PEi-D polymkeric substance, and it will be water-soluble but molecular weight generally will be lost during greater than about 750000 dalton.Water miscible forfeiture makes PEG or PEi-D polymkeric substance reduce the adaptability of patient's taste, and reduced to phosphate radical or oxalate in conjunction with effect.Because the polymer property of the water miscible PEG of the present invention or PEi-D polymkeric substance self and do not need metal ion in precipitate phosphoric acid root or oxalate process, preparation described in the invention obviously is better than all known or available preparations that are used for removing from gastro-intestinal system phosphate radical or oxalate.
At present known have many water-soluble polymerss, and the solvability of the polymkeric substance of higher molecular weight in water be usually less than the lower molecular weight with same composition polymkeric substance (referring to Thomson, R.A.M., " polymerization process of preparation water-soluble polymers ", the chemistry and technology of water-soluble polymers, Finch, C.A. edit Plenum, New York, NY, 1983, the 31-70 page or leaf, and Ruchs, O., " polymer solvent and non-solvent ", polymer handbook (Polymerhandbook), the 3rd edition, Brandrup, J. and Immergut, E.H. edit, Wiley, New York, New York, 1989, VII/379-VII/402 page).
Water-soluble polymers of the present invention is the sulfonamide derivatives (PEG-D) of polyoxyethylene glycol.The preparation of these polymkeric substance is with the epihalohydrin polymerization, and the polyepihalohydrin with gained carries out derivatize to obtain polyepihalohydrin derivative (PEi-D) polymkeric substance then.(the preparation condition back of PEi-D polymkeric substance will provide).The present industrial method for preparing polyepihalohydrin can obtain molecular weight ranges be lower than about 3000 short polymer chain or molecular weight ranges greater than 1000000 polymkeric substance (referring to E.J.Vandenberg, polymer science magazine (J.Polym.Sci.) 47,486-489 (1960); Vandenberg, E.J. " Elastomers, Synthetic (Polyethers) ", the Kirk-Othmer encyclopedia of chemical technology, the third edition, the 8th volume, Kroschwitz, J. edits, Wiley, New York, New York, 1979,568-582 page or leaf; And Owens, K., Kyllingstad, V.L. " Elastomers, Synthetic (Polyethers) ", the Kirk-Othmer encyclopedia of chemical technology, the 4th edition, the 8th volume, Kroschwitz, J. edits, Wiley, New York, NY, 1993,1079-1093 page or leaf).Therefore, the present invention also provides the preparation method of molecular weight ranges at 5000 to 750000 daltonian polyepihalohydrin sulfonamide derivatives (PEi-D) polymkeric substance.These PEi-D polymkeric substance are specially adapted to prevent that phosphate radical in the diet or oxalate are by the absorption of gastro-intestinal system.
The present invention relates to be respectively applied for phosphate radical or the water-soluble PEi-D polymkeric substance of oxalate coordinate and they and reduce in the diet phosphate radical or oxalate by the purposes of the absorption of gastro-intestinal system.This class PEi-D polymkeric substance can be by main polymer chain skeleton, the substituting group that is connected with main chain backbone, improve water miscible functional group and described with phosphate radical or oxalate coordinate functional group.
Water-soluble coordination PEi-D polymkeric substance of the present invention contain have or provide water-soluble and with the main chain of the coordination ability of phosphate radical or oxalate, or have give the polymer water dissolubility and can carry out functionalization with the main chain of phosphate radical or oxalate coordinate side chain, and molecular-weight average is preferably about 5000 to about 750000 dalton, particularly about 10000 to about 80000 daltonian polymkeric substance.PEi-D polymkeric substance of the present invention water-soluble is defined as the ability that polymkeric substance and water form the homogeneous mixture of the polymkeric substance that contains significant quantity.Preferably, water-soluble should be of PEi-D polymkeric substance of the present invention can be dissolved at least 0.01 gram polymkeric substance in 1000 ml waters, particularly can dissolve at least 1 gram polymkeric substance in 1000 ml waters.The reduction that phosphate radical or oxalate absorb in gastro-intestinal system is represented is when adopting PEi-D polymkeric substance of the present invention, and phosphate radical in the diet or oxalate absorb the percentage ratio that leaves gastro-intestinal system when not adopting polymkeric substance by health percentage ratio is little.This reduction can be when relatively animal be taken in the PEi-D polymkeric substance in the animal excrement percentage ratio and the animal of food phosphates root or oxalate do not take in this polymkeric substance or any other phosphate radical or the identical percentage ratio during the oxalate coordination agent determine.The variation that phosphate radical in process of growth or oxalate absorb can be by testing comparative descriptions in the blank animal.The reduction that phosphate radical or oxalate in the animal intestines and stomach system are absorbed can by through several weeks oral polymkeric substance before and among, the excretion of phosphate radical in the urine or oxalate is accounted for the phosphate radical that eaten or the percentage ratio of oxalate compares and further proved conclusively, this be because the quantity not sufficient of working as the phosphate radical that absorbed or oxalate with keep with urine normally in during the running balance of phosphate radical between the drainage of phosphate radical or oxalate or oxalate, the excretion of phosphate radical or oxalate will reduce in the urine.The reduction that phosphate radical or oxalate absorb in gastro-intestinal system also can by measured before taking in polymkeric substance and among amount in the experimental animal serum further proved conclusively.
The example of the polymkeric substance that the present invention is included be have can be improved water-soluble and with the water-soluble polymers of polyoxyethylene glycol (PEG-D) main chain backbone of functional group's derivatize of phosphate radical or oxalate coordination ability.Some this polymkeric substance may require to contain provide water-soluble or with the side chain of the functional group of phosphate radical or oxalate coordination ability.The present invention includes this two kinds of derived polymers (PEG-D).Can improve water-solublely, with the coordination ability of phosphate radical or oxalate, or the example of both side chains of having both at the same time comprises, or directly or pass through C 2-C 6Alkylidene group or (C 2-C 6Alkyl) functional group that links to each other with the main polymer chain skeleton of aryl is as the combination of hydroxyl, sulfonate radical, phosphonate radical, nitro, amido, phosphino-, carbonyl, sulfydryl, halogen and a plurality of these groups.The example of these polymer lateral chains should not be counted as the restriction to side chain of the present invention or functional group only as example.In order to reduce the taking dose of animal, its monomer that constitutes polymkeric substance of preferred polymkeric substance of the present invention has alap molecular weight usually.
A kind of method for preparing polyethylene glycol backbone skeleton (PEG) is that epihalohydrin such as Epicholorohydrin are being carried out polymerization in the presence of medium tenacity lewis acidic in a kind of solvent that does not play the chain terminator effect.An example of this solvent is a methylene dichloride, but alcohols or aqueous solvent are inapplicable as polymer solvent.This method is this professional known method, for example referring to U.S. patent 2,871,219 or E.J.Xandergerg, and polymer science magazine, 47,486-489 (1960).The advantage of this special methods is that the side chain that prepared polyethylene glycol backbone skeleton contains the functionalization that is connected in main chain backbone (is CH 2Cl), its other functional group that can easily will be narrated by the back replaces.It is 3 that another kind can be used on the monomer for preparing the polyethylene glycol backbone skeleton that contains the functionalization side chain in the similar reaction, 4-two chloro-1,2-butylene oxide ring (3,4-dichloro-1,2-butane oxirane).Other preparation method with polyethylene glycol backbone skeleton of the side chain that is connected on the main chain backbone so that polymkeric substance is carried out further functionalization is also included among the present invention.These methods are included on the polyoxyethylene glycol of previous formation carries out the dehydrogenation reaction of carbon-carbon bond and introduces functional group by two keys subsequently.The starting raw material of a preferred preparation polyethylene glycol backbone skeleton is epihalohydrin such as Epicholorohydrin or epibromohydrin.
As previously mentioned, polymkeric substance of the present invention is preferably water miscible.Some main polymer chain skeleton provides water-soluble.Sauerstoffatom in the various polyethylene glycol backbone skeletons can improve water-soluble.Some polymkeric substance may rely on the functionalization of side chain to improve that it is water-soluble.But for improve water-soluble functionalization to the main polymer chain skeleton can by in main chain backbone, introduce with water hydrogen bond action is arranged or in water the group of ionic dissociation realize.This class group comprises hydroxyl, amido, sulfonate radical, phosphate radical, carbonyl, carbamate groups, nitro and carboxyl.These examples only as improving the example of water miscible functional group, should not be counted as the restriction to functional group of the present invention.By adopting the monomer methods that has contained these groups during polymkeric substance, or these groups can be introduced in the polymkeric substance as functional group by method from the independent reaction of group to polymkeric substance that introduce in preparation.The example of preceding a kind of method is preparation polyvinylsulfonic acid and polyacrylic acid.This method is known by people in polymerization technique.
Second method is to introduce needed functional group in polymkeric substance by the conversion of already present functional group in the polymkeric substance.The conversion of this functional group is known by people in organic chemistry.For example, organic conversion complete works: functional group prepares guide (Comprehensive OrganicTransformation:A Guide to Functional Group), and the preparation approach of many introducing different functional groups is arranged among the Richard C.Larock.The form that contains in this book has been enumerated needed functional group, existing functional group and the serial response of this conversion of realization reported.Other document of report preparation method comprises Advanced Organic Chemistry: reaction, mechanism and structure, (Advanced Organic Chemistry:Reactions, Mechanisms, andStructure) the 4th edition, Jerry March; Nitrated: method and mechanism (Nitration:Methods and Mechanisms), Georga A.Olan, Ripudaman Malhotra and Subhash C.Narang; And Advanced Organic Chemistry (Advanced OrganicChemistry), Francis A.Carey and Richard J.Sundberg, Plenum Press, NY, 1990.
As mentioned above, polymkeric substance of the present invention also has and phosphate radical or oxalate coordinate ability.For this reason, the main chain backbone of polymkeric substance or contain and phosphate radical or oxalate coordinate group, or by this functional groupization.Anyly be cationic group and generally all help coordination with phosphate radical or oxalate being in (pH about 6.5 to 7.5) under the physiological pH.Amine and phosphine are this examples that can be cationic group under physiological pH.For with phosphate radical or oxalate coordination, amine should be quaternary ammonium compound, or can be converted into quaternary ammonium compound under physiological environment.Similarly, in order to be cation state, phosphine should be the level Four phosphine, or can easily be converted into the level Four phosphine under physiological environment.Therefore, amine can be primary amine, secondary amine, tertiary amine and quaternary ammonium compound or polyamines.Preferred functional group comprises that those are selected from ammonia, ethylene-amines, alkanol amine and (C 1-C 10Alkyl) group of amine.The preparation feedback of introducing these groups can improve the reference of water soluble group referring to aforementioned introducing.
Therefore, polymkeric substance of the present invention (PEG-D) can prepare by a step or two-step reaction.
Single stage method: when monomer contains suitable functional group, can form the suitable polymers main chain backbone and form simultaneously by polymerization and contain can be with the side chain of phosphate radical or oxalate coordinate functional group the time, can by single stage method prepare water miscible and phosphate radical coordinate polymkeric substance or with oxalate coordinate polymkeric substance.Main chain backbone, side chain or both should be able to be water-soluble.
Two-step approach: in two-step approach, the first step is the main chain backbone that preparation contains suitable leavings group.These leavings groups were substituted in second step and to introduce needed raising water-soluble, improved coordination ability or functional group that both have both at the same time.
Another aspect of the present invention is these PEG-D or PEi-D polymkeric substance as phosphate radical or the oxalate purposes that in gastro-intestinal system absorb of non-internal-absorting preparation in preventing diet.In this application, the water-soluble and size of polymkeric substance is found to be simultaneously and plays an important role.As mentioned above, water-soluble promotion coordination agent mixes with target compound, achieves more effective coordination.The water-soluble in addition taste that can improve preparation is accepted patient Geng Yi.Bulk of molecule is very important in this application, because can enter in the blood by the gastro-intestinal system absorption less than about 1500 daltonian molecules, this is not the desirable result of the present invention.Size is positioned at 1500 to 5000 daltonian molecules and is not absorbed by gastro-intestinal system, makes water enter phenomenon in the intestines but may cause infiltration, and causes the possibility of dysentery and dehydration.Usually can reduce along with the increase of polymer molecule is water-soluble.Therefore, except above-mentioned molecular weight lower bound, the molecular weight height of polymkeric substance of the present invention is limited to about 750000 dalton.
Concerning some polymkeric substance, adopt known method can obtain the main chain backbone of appropriate length.For example, with the vinyl pyrrolidone polymerization and subsequently with the size exclusion film or prepare the molded dimension exclusion chromatography mixture of the different molecular weight of gained is separated, obtain having the Polyvinylpyrolidone (PVP) of suitable molecular weight.Other polymkeric substance with suitable molecular weight can be by the mole preparation recently of correctly selecting monomer and catalyzer in the initial action mixture.But some polymkeric substance is difficult to obtain the molecular weight of required scope.These polymkeric substance usually need highly active catalyzer come initiated polymerization, but what obtained before side reaction stops polymerization only is very short polymkeric substance.When the catalyzer of these polyreactions by the part passivation when attempting that controlled polymerization is spent better, what in fact reaction obtained is very large molecular weight, uncontrollable at all polymkeric substance.These conclusions are known by those skilled in the art, and at contemporary polymer chemistry (second edition) (Allcock, H.R. and Lampe, F.W., Contemporary Polymer Chemistry, Second Edition, Prentice Hall, Englewood Cliffs, New Jersey, 1990, the 21-333 page or leaf) and polymkeric substance introduction (second edition) (Young, R.J. and Lovell, P.A., Introduction to Polymers, Second Edition, Chapman and Hall, NewYork, 1991,15-133 page or leaf) discusses in.For example those isolation technique that are used to separate Polyvinylpyrolidone (PVP) polymkeric substance that can successfully be used for handling high-polymerization degree with separate those low-molecular-weight polymkeric substance.
One embodiment of the invention be molecular weight more than or equal to 5000 dalton, preferably at least 12000 dalton, particularly at least 15000 daltonian Polyglycol 166-450 polymkeric substance (PEi-D polymkeric substance).The molecular weight of polymkeric substance of the present invention can be the arbitrary value that is higher than this minimum value, but simultaneously preferably less than 750000 dalton, is more preferably less than 500000 dalton, especially preferably less than 300000 dalton, especially less than 80000 dalton.Generally speaking, do not obtain the Polyglycol 166-450 polymkeric substance of molecular weight within preferred range of the present invention at present as yet.The molecular weight of the Polyglycol 166-450 polymkeric substance that a lot of existing technology is reported is low excessively, usually less than 3000 dalton (referring to T.Aida etc., macromole (Macromolecules) 21,1195-1202 (1988); A.Le Borgne etc., macromolecular chemistry, macromole collection of thesis (Makromol.Chem, Macromol.Symp.) 73,37-46 (1993); With R.Nomure etc., polymer chemistry magazine (J.Polym.Chem.) 26,627-636 (1988)).These polymkeric substance normally prepare as aluminum alkyls or boron compound with very active catalyzer.When adding oxygenatedchemicals with the part catalyst deactivation in Al catalysts, the molecular weight of resulting Polyglycol 166-450 surpasses 1000000 dalton (referring to U.S. Patent No. 2,871,219; E.J.Vandenberg, polymer science magazine 47,486-489 (1960); With J.Wu etc., polymkeric substance magazine (Polym.J.) 22,326-330 (1990)).
The present invention finds that the Polyglycol 166-450 with suitable molecule weight range can pass through to adopt hexafluorophosphoric acid triethyl oxygen (triethyloxioniumhexafluorophosphate) or two (trifluoromethanesulfonic acids 1,2-second diester) (1,2-ethyl di (trifluoromethanesulfonate), promptly 1,2-ethyl ditriflate) catalyzer prepares.Hexafluorophosphoric acid triethyl oxygen it is reported it is a kind ofly can make Epicholorohydrin polymeric catalyzer by each the end addition Epicholorohydrin base to center ethylene glycol, the molecular weight that obtains is that 900 to 1000 dalton are (referring to Okamoto, Y., " there is the positively charged ion ring-opening polymerization of Epicholorohydrin down in ethylene glycol ", ring-opening polymerization: kinetics, mechanism and synthetic (Ring-opening Polymerization:Kinetics, Mechanisms, andSynthesis), McGrath, J.E. edit ACS, Washington, C.C.1985,286:381-372).The present invention relates to not have the preparation of the Polyglycol 166-450 under the ethylene glycol existence.The present invention obtains the Polyglycol 166-450 of suitable molecular weight by the controlled polymerization termination reaction.This control is anhydrated to remove by carefully distilling all reactants and solvent, carefully in exothermal reaction process controlled temperature and when reaction is initial clearly the ratio of control catalyst molecule and Epicholorohydrin molecule realize.After the polymer growth chain of setting number is initiated, in reaction mixture, add Epicholorohydrin continuously and also can carry out best control the molecular weight of polymkeric substance.The method of the Polyglycol 166-450 of another kind of preparation desired molecule amount is to adopt two (trifluoromethanesulfonic acids) 1, and 2-second diester is as catalyzer.Method of the third preparation molecular weight Polyglycol 166-450 within the required range is to adopt fluoroboric acid as catalyzer and suitably controlled temperature and feed rate.
Hold concurrently and sometimes, can in the reaction of second step, on main chain backbone, generate various functional groups when needs improve water-soluble, coordination ability or both, as amido, amino acid based, crown ether, nitrogen heterocyclic ring or carboxylate radical.The required activity of water-soluble ligand polymer of gained is depended in the selection of functional group.Required functional group preferably cooperates the site to carry out coordination with phosphate radical or oxalate under to a mole of phosphoric acid root or oxalate at one mole monomer, and the quantity of the required polymkeric substance of unitary dose can be dissolved in as in 1 to 8 ounce the less water as 1 to 10 gram.Ideal situation is that this two kinds of effects can play in a kind of functional group, but also may generate two or more different functional group on the main polymer chain skeleton.Generating one or more required dentates on the polyethylene glycol backbone skeleton is to realize by the suitable reaction that the characteristic by kind of synthesizing the functional group in the post polymerization thing and required dentate determines.In the embodiment preferred of the present invention that the main polymer chain skeleton is prepared by Epicholorohydrin, the functionalization of Polyglycol 166-450 is by it is reacted to provide the required activity of water-soluble chelating polymer intended use to realize with a kind of suitable amine under the nucleophilic condition therein.For example, if only need be in conjunction with phosphate radical under sour environment, acid can be with the positively charged ammonium ion of the protonated generation of amine so, and it will be in conjunction with the negative ion as phosphate radical or oxalate.Therefore; adopt primary amine or secondary amine (as quadrol, diethylenetriamine as starting raw material; or primary amine protected to impel the secondary nitrogen-atoms to replace; or the higher homologue of ethyleneamines) just enough; one of them nitrogen-atoms replace chlorine atom, and other nitrogen-atoms still keeps carrying out protonated and in conjunction with the free state of negative ion.Even come the replace chlorine atom, also can access and to carry out protonated amine with ammonia.On the other hand, even under alkaline condition (for example because of taking Tagamet TMWhen not having in the patient's that hydrochloric acid in gastric juice exists the gastro-intestinal system in the body in conjunction with phosphate radical), if desired in conjunction with phosphate radical, can adopt tertiary amine such as Trimethylamine 99 to come the replace chlorine atom.Will generate a positively charged quaternary ammonium compound that has nothing to do with pH like this.Therefore, for example, the polymkeric substance with following formula should be an example of polymkeric substance of the present invention:
Figure A9719995400191
Wherein each R can be H independently of one another, the unsubstituted C of non-branching, branching or cyclic 1-C 6Alkyl, the C that non-branching, branching or cyclic replace 1-C 6Alkyl, unsubstituted C 6-C 14Aryl, the C of replacement 6-C 14Aryl, or 1 or 2 R base do not exist, and for example has 1 R base not exist, and described in this case nitrogen-atoms only has 3 substituting groups (comprising the substituting group that connects the main polymer chain skeleton) rather than 4 substituting groups.For example, when quadrol substituted onto on the Polyglycol 166-450, it was H that its expression formula should be a R, and a R is an amino-ethyl, also had a R not exist.In another example, Trimethylamine 99 substitutes onto on the Polyglycol 166-450, and three R bases in its above-mentioned expression formula are methyl.Also have an example, when hexadecylamine substituted onto on the Polyglycol 166-450, then a R base was a hexadecyl in the expression formula, and a R base is H, and another R base does not then exist.
When title complex requires highly selective or high stability, Polyglycol 166-450 or other water-soluble polymers can be substituted with the macrocylc compound that contains oxygen, nitrogen, sulfur heteroatom or these heteroatomic combinations in the big ring, as crown ether, Azacrown ether containing, thia crown ether, cyclodextrin or porphyrin (for example, referring to R.M.Lzatt etc., chemistry summary (Chem.Rev.) 91,1721-2085 (1991); With S.Tamagaki etc., Supramol.Chem.4,159-164 (1994)).When big ring dentate substitutes onto on the polymkeric substance, may need other functional group to guarantee the water-soluble of polymkeric substance.
The PEi polymkeric substance according to mode discussed above through derivatize to form their corresponding PEi-D polymkeric substance.When amino was required as the functional group in the derivative, PEi can react in pure amine solvent.The minimum dosage of amine is generally 4 times of molar excess of chloromethyl among the PEi, preferred 12 to 16 times of molar excess.An exception of this mole required amount is a Trimethylamine 99, in 25% aqueous solution every mole PEi only need be less to 0.5 mole Trimethylamine 99.The common requirement of reaction system is anhydrous in this step reaction, because hydrolysis reaction can take place the chloromethyl among the PEi.Temperature of reaction is about 25 to about 120 ℃.The reaction of back is carried out described in aforementioned and embodiment.The transformation efficiency that chlorine in the Polyglycol 166-450 in the chloromethyl is converted into sulfonamide derivatives is about 10 to about 80%.
The present invention obtains further instruction by the following examples, and these embodiment only are intended for example of the present invention.General experimental procedure
The step that adds the quantity of amine in A, the mensuration Polyglycol 166-450 (PEi)
The quantity of quadrol in the Polyglycol 166-450 polymkeric substance (EDA) functionalization adopts the titrating method of copper to measure.At Murexide TMThe existence of indicator is down with Cupric Chloride Solution titration PEi/EDA solution.Cupric ion is by the EDA chelating, up to excessive copper and indicator coordination in saturated, observes this terminal point with photoelectric color comparator.
METTLER DL40GP Memo titration apparatus solutions employed has:
1,0.01M Cupric Chloride Solution adds 1.705 gram (0.01 mole) cupric chloride (CuCl in 1 liter of volumetric flask 22H 2O, Fisher company, molecular weight 170.48), be diluted to scale with deionized water.
2,0.002M sodium acetate buffer solution adds 0.272 gram (0.002 mole) sodium acetate trihydrate (CH in 1 liter of volumetric flask 3COONa3H 2O, Fisher company, molecular weight 136.08), be diluted to scale with deionized water.
3,0.1%Murexide TMIndicator solution adds 5.0 gram (0.0176 mole) purple carmines (Fisher company, molecular weight 284.19) in 500 milliliters of volumetric flasks, be diluted to scale with deionized water.
With volume is that 125 milliliters of disposable polyethylene specimen beakers are at METTLER Weigh on the AE163 balance, and add the PEi/EDA aqueous solution (estimating about 8 milligrams of PEi/EDA).Use METTLER Method 365 on the DL40GP Memo titration apparatus is the weight of record sample automatically.In this PEi/EDA solution, add 80 ml deionized water, 4.0 milliliter of 2 mmole/rise aqueous sodium acetate solution and the 0.5 milliliter of 0.1% purple carmine aqueous solution (Murexide TMIndicator).Sample is positioned on the sample changer and carries out titration with the 0.01M Cupric Chloride Solution.Use METTLER DP550 Phototrode photoelectric color comparator is observed titration end point, and enters in the Memo titration apparatus.The quantity of functional group can be calculated according to the mole number with the cupric ion of EDA chelating in the Polyglycol 166-450 polymkeric substance.An example of this titration method can see the following form:
The data of table 1, quadrol and Polyglycol 166-450 reaction
Reaction numbering # EDA: Polyglycol 166-450 mol ratio Temperature (℃) Molecular weight by the filter membrane dialysis Strength of solution (%) Example weight (gram) Titer (milliliter) Join the percentage ratio of EDA in the Polyglycol 166-450
?53554-40a 16 108 1,000 6.6 0.1254 2.460 34.54
?53554-40b 16 108 3,500 7.1 0.1123 2.320 33.80
?53554-40c 16 108 12-14,000 3.6 0.2064 2.203 34.54
?53554-41a 4 25 1,000 10.8 0.0680 0.735 11.63
?53554-41b 4 25 3,500 10.2 0.0800 0.800 11.39
?53554-41c 4 25 12-14,000 7.2 0.1132 0.842 12.00
From the data of top table 1 as can be seen, be used for the quadrol (EDA) of Polyglycol 166-450 polymkeric substance (PEi) reaction manyly more, temperature of reaction is high more, and the quantity of the EDA that is added on the main polymer chain skeleton is just many more.From adopting a large amount of experiments that various amine carries out functionalization with the Polyglycol 166-450 polymkeric substance as can be seen, the quantity that is connected to amine on the PEi polymkeric substance is many more, polymkeric substance water-soluble just high more.PEi/EDA solution greater than 50% (weight) can at room temperature obtain.
The step of B, usefulness gel permeation chromatography molecular weight.In order before any derivative reaction, to measure the molecular weight of Polyglycol 166-450, adopt PL-gel Mixed E chromatographic column, make sample solvent and elutriant with tetrahydrofuran (THF).Flow rate is controlled at 1 ml/min, and column temperature is 40 ℃.Sample is dissolved in the tetrahydrofuran (THF) with the concentration of 0.25% (weight), removes by filter any graininess precipitation (polymkeric substance that wherein may comprise some very high molecular weights).Adopt the compensation syringe that 150 microlitre solution are injected chromatographic column.The software that computerizeds control in the device according to the color atlas of gained obtains M by mathematical computations n, M w, M zAnd M Z+1All molecular weight are with M wRepresent.
Mensuration through the molecular weight of the Polyglycol 166-450 polymkeric substance of functionalization adopts the TSKgel2000PW+3000PW+5000PW chromatographic column, is that 0.1M NaCl and concentration are that 1/1 the methanol system of 0.1M EDA is an eluting solvent with containing concentration, and column temperature is 40 ℃.The injection liquid volume is 100 microlitres.Sample is soluble in water with 1% concentration, filters before injection.With M wCome reporter molecule amount data.
The present invention obtains further instruction by the following examples, and these embodiment only are intended for example of the present invention.Embodiment starting raw material embodiment A: prepare Polyglycol 166-450 (PEi) with hexafluorophosphoric acid triethyl oxygen
In anhydrous air, 0.1257 gram hexafluorophosphoric acid triethyl oxygen is dissolved in the 9.4438 gram anhydrous methylene chlorides.Distilled Epicholorohydrin (78.4 gram) adding is immersed in the container of 40 ℃ of usefulness dry nitrogen purges in the thermostatic bath.Under agitation hexafluorophosphoric acid triethyl oxygen solution is joined in the Epicholorohydrin, and keep reaction 24 hours.When reaction mixture becomes sticky, temperature is increased to 70 ℃.Washing with alcohol three times of the material of gained.Obtain 48 gram materials.Gel permeation chromatography shows that its molecular weight is 3000 to 400000 dalton, and the molecular weight of middle peak value (Mw) is 100000 dalton, and the molecular weight of 90% polymkeric substance is between 5000 to 100000 dalton.Embodiment B: adopt fluoroboric acid to prepare Polyglycol 166-450 (PEi)
In anhydrous air, with the mixture heating up to 40 of the diethyl ether solution of 450 milliliters of methylene dichloride, 1.0 milliliter of 48% fluoborate aqueous solution and 10 milliliter of 54% fluoroboric acid ℃.850 milliliters of Epicholorohydrins of slow adding and backflow are finished until reaction in this mixture.With Rotary Evaporators in decompression with under 100 ℃ the temperature solvent in the reaction system is removed at the most, till therefrom can't steaming solvent again.Gel permeation chromatography shows that the molecular weight of polymkeric substance is 3500 dalton (M n), the molecular weight of the material above 40% is more than 14000 dalton.End product embodiment 1: the preparation of Polyglycol 166-450/Trimethylamine 99 (PEi/TMA)
In one 2 liters stainless steel PARR voltage-resistant reactor, add the molecular weight of 185 grams (2 moles) greater than 5000 daltonian Polyglycol 166-450 polymkeric substance (molecular weight of repeating unit is 92.53).Trimethylamine 99 (molecular weight the is 59.11) solution that in this Polyglycol 166-450 polymkeric substance, adds 246.5 gram (1 mole) 24% (weight) concentration.Reactor is sealed and is positioned in the PARR heated/stirred device, with nitrogen pressure to 75 pound/square inch (handkerchief).Under constant speed stirs, reaction vessel is heated to 115 ℃.Reactor kept 16 hours under the state of 115 ℃ and 75 pounds/square inch (handkerchief).With reactor cooling, open after being depressurized to air pressure.With the B filtration under diminished pressure reaction soln of No. 1 filter paper and 9.0 centimetres, transfer to then in 500 milliliters of round-bottomed bottles.The rotation evaporating solvent is 80 milliliters until liquor capacity under 70 ℃ and 8 inches (20.32 centimetres) water negative pressure.Reaction product is transferred to Spectra/Por TMIn the filter bag (the molecular weight threshold values is 14000), in the deionized water of 10 inches (25.4 centimetres), dialyse 16 hours to remove all unreacted small molecules.The molecular weight of resulting polymers is about 18000 dalton (M w).Embodiment 2: Polyglycol 166-450/Trimethylamine 99/ammonium hydroxide (PEi/TMA/NH 4OH) preparation
The Polyglycol 166-450 polymkeric substance (molecular weight of repeating unit is 92.53) that in one 2 liters stainless steel PARR voltage-resistant reactor, adds 23.6 grams (0.25 mole).Trimethylamine 99 (molecular weight the is 59.11) solution that in this Polyglycol 166-450 polymkeric substance, adds 250 ml waters and 30.8 gram (0.125 mole) 24% (weight) concentration.Reactor is sealed and is positioned in the PARR heated/stirred device, under constant speed stirs, reaction vessel is heated to 105 ℃.Reactor kept 16 hours under the state of 105 ℃ and 50 pounds/square inch (handkerchief).With reactor cooling, be depressurized to the solution of ammonium hydroxide that adds 450 grams (7.7 moles) 29% (weight) after the air pressure.Reactor is resealed, be positioned in the heated/stirred device and also be heated to 105 ℃ again.Reactor kept 16 hours under the state of 105 ℃ and 80 pounds/square inch (handkerchief).With reactor cooling, be depressurized to after the air pressure and unlatching subsequently.With the B filtration under diminished pressure reaction soln of No. 1 filter paper and 9.0 centimetres, transfer to then in 500 milliliters of round-bottomed bottles.The rotation evaporating solvent is 80 milliliters until liquor capacity under 70 ℃ and 23 inches (58.42 centimetres) water negative pressure.Reaction product is transferred to Spectra/Por TMIn the filter bag (the molecular weight threshold values is 3500), dialysis is 18 hours in the deionized water of 10 inches (25.4 centimetres).With the solution lyophilize, obtain shallow tan water absorbability solid then.Embodiment 3: the preparation of Polyglycol 166-450/diethylenetriamine (PEi/DETA)
On 500 milliliters of three mouthfuls of round-bottomed flasks, reflux condensing tube is installed, is connected with THERMOWARTCH I 2The thermometer of R temperature controller and dropping funnel.In this flask, add the diethylenetriamine (molecular weight is 103.2) of 412.7 grams (4 moles), be heated to 120 ℃ then.Add 37.7 gram (0.41 mole) molecular weight in the dropping funnel greater than 5000 Polyglycol 166-450 (the monomer molecule amount is 92.53).The speed about 0.25 milliliter with per minute joins Polyglycol 166-450 in the diethylenetriamine, subsequently reaction mixture is continued heating 60 minutes, is cooled to 45 ℃ then.50% aqueous sodium hydroxide solution (32.8 gram, 0.41 mole) is mixed with reaction mixture mutually with 150 ml waters and stirring 45 minutes, to remove white precipitate, is that 3500 daltonian Spectra/PorTM filter membranes dialyse with the molecular weight threshold values with filter paper filtering.Freeze-drying solution is to obtain white pulverulent material subsequently, and molecular-weight average is about 18000 dalton (M w).Embodiment 4: the preparation of Polyglycol 166-450/quadrol (PEi/EDA)
On 2000 milliliters of three mouthfuls of round-bottomed flasks, stirring rod, reflux condensing tube, 10 milliliters of dropping funnels are installed and are connected with THERMOWARTCH I 2The thermometer of R temperature controller.The quadrol (molecular weight is 60.1) that in this flask, adds 360 grams (6 moles).In dropping funnel, add 231 gram (2.5 moles) molecular weight greater than 5000 and about 40% molecule greater than 12000 daltonian Polyglycol 166-450 polymkeric substance (molecular weight of repeating unit is 92.53).Under constant speed stirs, will contain the reaction flask reflux (100 ℃) of EDA, under refluxing, the Polyglycol 166-450 polymkeric substance be joined in the quadrol with the about 4.5 milliliters speed of per minute.Add the back that finishes at all Polyglycol 166-450 polymkeric substance and continue reaction 16 hours.Then reaction mixture is transferred in the round-bottomed bottle and under the water negative pressure of 75 ℃ and 23 inches (58.42 centimetres) rotary evaporation to remove unreacted quadrol.It is 14000 daltonian Spectra/Por that Polyglycol 166-450/EDA solution is transferred to the molecular weight threshold values TMDialysed 18 hours in the filter bag and in 10 inches deionized water.Freeze-drying solution is to obtain shallow tan water absorbability solid subsequently.Gel permeation chromatography shows that molecular-weight average is greater than 17000 dalton (M w).Comparing embodiment D: the preparation of PAH biguanides (PAAG)
In a dry beaker, 9.36 gram PAH hydrochlorides (0.1 mole, Aldrich company produces, molecular weight is 50000 to 65000 dalton) are mixed with the NaOH solution of 20 milliliters of 10M and the water of capacity.The liquid decant is removed, washed with water resin and dry.Resin is suspended in round-bottomed flask in 300 ml methanol and mixes with 20.12 gram 3-1-carboxylic amidine nitrate (0.1 gram, 3,5-dimethylpyrazole-1-carboxamidine nitrate).With reaction mixture refluxed 96 hours.Then with resin filter, with methanol wash and dry.The molecular weight of product is greater than about 75000 dalton.Comparing embodiment E: the preparation of poly-(allyl amine-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate)
With molecular weight is that 52000 to 83000 daltonian PAH (1.88 gram, 0.02 mole) join in the reactor and with 40.4548 gram 3M NaOH solution (0.121 mole) and mix.Add N, N, N-trimethylammonium-oxyethane first ammonium muriate (N, N, N-trimethyl-oxiranemethanaminium chloride, 20.0150 restrain 65.2% solution, 0.086 mole) reaction mixture refluxed is spent the night, in being 3500 dialysis tubing, the molecular weight threshold values dialyses with deionized water.With the lyophilize of gained solution, obtain 1.9 gram brown solids.This solid is:
Figure A9719995400261
Its molecular weight is greater than 75000 dalton.Comparing embodiment F: the preparation of poly-(allyl group-N, N-dimethylamino-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate)
With molecular weight be 52000 to 83000 daltonian PAH (0.9356 gram, 0.01 mole) be dissolved in the 5 gram acetonitriles and with NaOH solution (0.0108 mole) reaction of 3.6 milliliters of 3M so that the pH value reaches 7.4.Add methyl iodide (2.84 grams, 0.02 mole) and make reaction mixture refluxed.In reflux course, other adds the NaOH solution (0.0024 mole) of 0.8 milliliter of 3M so that the pH value is brought up to 7.9.Add N, N, N-trimethylammonium-oxyethane first ammonium muriate (N, N, N-trimethyl-oxiranemethanaminium chloride, 5.77 grams, 65.2% solution, 0.025 mole) also continues to reflux.After 24 hours, it is also to use the deionized water dialysed overnight in the 3500 daltonian dialysis tubings that reaction mixture is placed on the molecular weight threshold values.With the lyophilize of gained solution, obtain 1.56 gram (58% productive rate) chocolate brown powder.This compound is:
Figure A9719995400262
Its molecular weight is greater than 75000 dalton.
Also have many other embodiment! Physiology EXAMPLE Example 1: adopt Polyglycol 166-450/quadrol to prevent the absorption of gastro-intestinal system phosphate radical
Contain 0.65gm% phosphorus blended grain mouse food and mix mutually according to the prepared Polyglycol 166-450/quadrol of the step of embodiment 4.The preparation of feed is the Polyglycol 166-450/quadrol of capacity to be eaten with mouse mix, so that every mole phosphate radical has 3 moles of binding sites in the mouse food, every mole phosphate radical has 1 mole binding site in the mouse food, every mole phosphate radical has in 0.5 mole binding site and the mouse food every mole phosphate radical that 0 mole binding site (blank) is arranged in the mouse food.Six mouse a meal every day are total to one week of feeding.In these processs of the test, in amount average out to 18.2 mg/day that finish phosphate radical in the space-time guinea pig urine week, amount average out to 8.7 mg/day of phosphate radical in the mouse urine of feeding 0.5 * dosage, amount average out to 8.6 mg/day of phosphate radical in the mouse urine of feeding 1 * dosage, and amount average out to 1.9 mg/day of phosphate radical in the mouse urine of feeding 3 * dosage.The low expression of phosphate content is in the urine, has kept phosphate radical by the restriction renal excretion, and mouse does not obtain enough food phosphates roots.Overall balance (diet absorption-urine excretion-defecate) at the last phosphate radical in a week is 47.8 mg/day for blank mouse, to feeding 0.5 * dosage mouse is 50.9 mg/day, to feeding 1 * dosage mouse is 34.3 mg/day, and is 39.5 mg/day to feeding 3 * dosage mouse.Comparative Example A An: adopt PAH (RenaStat TM) prevent the absorption of gastro-intestinal system phosphate radical
Molecular weight is that 50000 to 65000 daltonian PAH hydrochlorides are the Aldrich product, does not carry out further purifying in use.The mouse food that will contain the blended grain of 0.65gm% phosphorus restrains the mixed of powder mouse food to 1.96 gram polymkeric substance with the PAH hydrochloride according to 98.04, and each phosphate radical all has an amine binding site in the feed of gained.Arbitrarily feed two 125 mouse in the gram with this feed, and compare with two mouse arbitrarily feeding with original powder feed.Before beginning feeding this special diet and stable fed for two weeks after, every kind of mouse is separated by collected its ight soil and urine in 24 hours, and analyze the wherein amount of phosphate radical with the induced dipole plasma-speetrometer.Because blank mouse has been slowed down their growth after two weeks, the percentage ratio of the food phosphates root of finding in ight soil is increased to 72% (7% increasing amount) from 65%, and the excretion that the mouse of taking in the PAH hydrochloride demonstrates the food phosphates root is increased to 75% (17% increasing amount) from 58%, and phosphoric acid salt excretory increasing amount is 2.6 times of blank mouse.Meanwhile, phosphate radical accounts for the percentage ratio of taking in phosphate radical and is increased to 16% from 6% in the urine of blank mouse, and the mouse of taking in the PAH hydrochloride is reduced to 2% at the percentage ratio that the final stage of test then accounts for the phosphate radical of their urine excretion the phosphate radical that diet takes in from 6%.This shows, compares with blank mouse, and the mouse of taking in PAH has been maintained the content of phosphorus in the urine, illustrates that they can not absorb enough phosphate radicals from their diet.Embodiment II and Comparative Example A An: adopt the PAH biguanides to prevent the absorption of gastro-intestinal system phosphate radical
The oral Nulytely of Sprague Dawley mouse of two 125 grammes per square metres TMTo remove materials all in their gastro-intestinal systems.Afterwards, wherein a mouse adopts the gavage feeding to contain the milk of 0.324 mmole phosphate radical.Another kind of mouse is adopted the milk of the same amount of gavage feeding, but wherein is mixed with the prepared PAH biguanides of 0.0322 gram embodiment 5.After one hour, give two mouse feeding Nulytely TMTo remove and to collect all unabsorbed diet in their gastro-intestinal systems.Adopt the induced dipole plasma-speetrometer to measure the content of phosphate radical in the collected ight soil.The amount of taking the mouse institute excretory phosphate radical of PAH biguanides be blank mouse drain the phosphate radical amount 66%.Embodiment III and Comparative Examples B: adopt poly-(allyl amine-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate) that phosphate radical is carried out coordination
0.72 gram is dissolved in the solution of making 0.345M in 10 ml waters according to the step of embodiment 6 prepared poly-(allyl amine-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate).In in four test tubes each with 0.54 milliliter this solution (monomeric unit is 0.19 mmole) and 10 milliliters of 0.0207M NaH 2PO 4Mix mutually to make the pH value with an amount of HCl and NaOH be 3, the pH value is 4.5, the pH value be 6 and the pH value be 7.5 solution.With 10 milliliters of 0.0207M NaH 2PO 4With 0.50 milliliter of 1.5M CaCO 3The test tube liquid that (0.749 mmole) preparation has identical pH value.With sodium radio-phosphate,P-32 solution and regulate the pH value and prepare blank test tube liquid.All test tubes are all used the dilution of 12 ml waters.With test tube vigorous stirring 1 hour.Subsequently solution is transferred to Centricon respectively TMIn the different test tubes of 30 molecular weight threshold values and from 30 minutes.The filtrate of collecting is analyzed the content of its phosphate radical with the induced dipole plasma spectrometer.In the pH value is that 3 o'clock polymkeric substance are removed 58% phosphate radical, is to remove 59% phosphate radical at 4.5 o'clock in the pH value, most removes 56% phosphate radical at 6 o'clock at pH, and is to remove 44% phosphate radical at 7.5 o'clock in the pH value.In the pH value is that 3 o'clock lime carbonate is removed 16% phosphate radical, is to remove 13% phosphate radical at 4.5 o'clock in the pH value, most removes 9% phosphate radical at 6 o'clock at pH, and is to remove 7% phosphate radical at 7.5 o'clock in the pH value.The result of blank test tube is, is to remove 0.7% phosphate radical at 3 o'clock in pH value, the pH value be 4.5 o'clock except that 1.1% phosphate radical, most removed 0.4% phosphate radical at 6 o'clock at pH, and be to remove 0.6% phosphate radical at 7.5 o'clock in the pH value.Therefore, poly-(allyl amine-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate) is a kind of effective coordination agent of phosphate radical.Embodiment IV and comparing embodiment C: adopt poly-(allyl group-N, N-dimethylamino-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate) that phosphate radical is carried out coordination
0.72 gram is dissolved in the solution of making 0.263M in 10 ml waters according to the step of embodiment 7 prepared poly-(allyl group-N, N-dimethylamino-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate).In in four test tubes each with 0.67 milliliter this solution (monomeric unit is 0.18 mmole) and 10 milliliters of 0.0207M NaH 2PO 4Mix mutually to make the pH value with an amount of HCl and NaOH be 3, the pH value is 4.5, the pH value be 6 and the pH value be 7.5 solution.With 10 milliliters of 0.0207M NaH 2PO 4With 0.50 milliliter of 1.5M CaCO 3The test tube liquid that (0.749 mmole) preparation has identical pH value.With sodium radio-phosphate,P-32 solution and regulate the pH value and prepare blank test tube liquid.All test tubes are all used the dilution of 12 ml waters.With test tube vigorous stirring 1 hour.Subsequently solution is transferred to Centricon respectively TMIn the different test tubes of 30 molecular weight threshold values and centrifugal 30 minutes.The filtrate of collecting is analyzed the content of its phosphate radical with the induced dipole plasma spectrometer.In the pH value is that 3 o'clock polymkeric substance are removed 49% phosphate radical, is to remove 53% phosphate radical at 4.5 o'clock in the pH value, most removes 48% phosphate radical at 6 o'clock at pH, and is to remove 39% phosphate radical at 7.5 o'clock in the pH value.In the pH value is that 3 o'clock lime carbonate is removed 16% phosphate radical, is to remove 13% phosphate radical at 4.5 o'clock in the pH value, most removes 9% phosphate radical at 6 o'clock at pH, and is to remove 7% phosphate radical at 7.5 o'clock in the pH value.The result of blank test tube is, is to remove 0.7% phosphate radical at 3 o'clock in pH value, the pH value be 4.5 o'clock except that 1.1% phosphate radical, most removed 0.4% phosphate radical at 6 o'clock at pH, and be to remove 0.6% phosphate radical at 7.5 o'clock in the pH value.Therefore, poly-(allyl group-N, N-dimethylamino-N-(2-hydroxyl-3-TMA (TriMethylAmine) propyl group) muriate) is a kind of effective coordination agent of phosphate radical.Embodiment V: Polyglycol 166-450/EDA and Polyglycol 166-450/DETA are to the coordination of oxalate
The ammonium oxalate solution of preparation 0.025M.Step according to embodiment A prepares Polyglycol 166-450, and its molecular weight is about 45000 dalton.Preparation EDA derivative (previous embodiment 4) and EDTA derivative (previous embodiment 3).With these two kinds of derivative solutions (Centricon in one molecular weight threshold values strainer TMConcentrating instrument) introduces 0.001 mole binding site, then 0.001 mole oxalate is joined in only aqueous blank of each enriched material neutralization.Carry out the solution mixing centrifugal after one hour.Adopt application of gas chromatorgraphy/mass (GC-MS) analyze filtrate oxalate amount and compare with the enriched material that only contains oxalate.EDA and DETA derivative polymer have all absorbed about 30% oxalate.Embodiment VI: adopt Polyglycol 166-450/Trimethylamine 99/ammonia to prevent the absorption of gastro-intestinal system phosphate radical
The mouse food that will contain the blended grain of 0.65gm% phosphorus restrains the mixed of powder mouse food to 2.36 gram polymkeric substance with Polyglycol 166-450/Trimethylamine 99/ammoniacal liquor that embodiment 2 prepares according to 97.64, and each phosphate radical all has an amine binding site in the feed of gained.Arbitrarily feed two 125 mouse in the gram with this feed, and compare with two mouse arbitrarily feeding with original powder feed.Before beginning feeding this special diet and stable fed for two weeks after, every kind of mouse is separated by collected its ight soil and urine in 24 hours, and analyze the wherein amount of phosphate radical with the induced dipole plasma-speetrometer.Because blank mouse has been slowed down their growth after two weeks, the percentage ratio of the food phosphates root of finding in ight soil is increased to 72% (7% increasing amount) from 65%, and the excretion that the mouse of taking in Polyglycol 166-450/Trimethylamine 99/ammoniacal liquor demonstrates the food phosphates root is increased to 76% (11% increasing amount) from 65%, and phosphoric acid salt excretory increasing amount is 1.6 times of blank mouse.Meanwhile, phosphate radical accounts for the percentage ratio of taking in phosphate radical and is increased to 16% from 6% in the urine of blank mouse, and the phosphate radical of taking in mouse urine under normal diet of Polyglycol 166-450/Trimethylamine 99/ammoniacal liquor accounts for the phosphate radical 7% that diet is taken in, and accounts for the phosphate radical 10% that diet is taken at the phosphate radical of the final stage urine of testing.Therefore, this shows that the mouse of absorption Polyglycol 166-450/Trimethylamine 99/ammoniacal liquor and blank mouse relatively have been maintained the content of phosphorus in the urine, illustrates that they can not absorb enough phosphate radicals from their diet.Embodiment VII: adopt Polyglycol 166-450/Trimethylamine 99 to prevent the absorption of gastro-intestinal system phosphate radical
The mouse food that will contain the blended grain of 0.65gm% phosphorus restrains the mixed of powder mouse food to 3.18 gram polymkeric substance with Polyglycol 166-450/Trimethylamine 99 that embodiment 1 prepares according to 96.82, and each phosphate radical all has an amine binding site in the feed of gained.Arbitrarily feed two 125 mouse in the gram with this feed, and compare with two mouse arbitrarily feeding with original powder feed.Before beginning feeding this special diet and stable fed for two weeks after, every kind of mouse is separated by collected its ight soil and urine in 24 hours, and analyze the wherein amount of phosphate radical with the induced dipole plasma-speetrometer.Because blank mouse has been slowed down their growth after two weeks, the percentage ratio of the food phosphates root of finding in ight soil is increased to 72% (7% increasing amount) from 65%, and the mouse of taking in Polyglycol 166-450/Trimethylamine 99 demonstrates the excretion of food phosphates root and is reduced to 59% (3% reduction amount) from 62%.Meanwhile, phosphate radical accounts for the percentage ratio of taking in phosphate radical and is increased to 16% (10% increasing amount) from 6% in the urine of blank mouse, and the phosphate radical of taking in mouse urine under normal diet of Polyglycol 166-450/Trimethylamine 99 accounts for the phosphate radical 6% that diet is taken in, and accounts for the phosphate radical 9% (3% increasing amount) that diet is taken at the phosphate radical of the final stage urine of testing.This moderate increase shows, compares with blank mouse, and the mouse of taking in Polyglycol 166-450/Trimethylamine 99 has been maintained the content of phosphorus.
Through to the detail knowledge of specification sheets disclosed herein and invention example, other embodiment of the present invention is conspicuous for those skilled in the art.It only is example of the present invention that this specification sheets and these embodiment should be counted as, and real scope of the present invention and feature are illustrated in the claim of back.

Claims (28)

1, a kind of water-soluble poly ether diol polymer, contain: the main chain backbone by carbon atom and Sauerstoffatom constitute, wherein contain at least two successive carbon atoms between each Sauerstoffatom; Group on the main polymer chain skeleton, or the functionalization deriveding group on the polymkeric substance, it also can carry out coordination with phosphate radical or oxalate for positively charged ion under the physiological pH value; With molecular-weight average be about 5000 to about 750000 dalton.
2, the polymkeric substance of claim 1, its molecular-weight average are about 10000 to about 750000 dalton.
3, the polymkeric substance of claim 2, its molecular-weight average are about 12000 to about 300000 dalton.
4, the polymkeric substance of claim 2, its molecular-weight average are about 15000 to about 80000 dalton.
5, the polymkeric substance of claim 1, wherein polymkeric substance is by institute of functional group derivatize.
6, the polymkeric substance of claim 5, functional group or directly link to each other wherein with the main polymer chain skeleton, or pass through C 2-C 6Alkylidene group or C 2-C 6Alkyl-C 6-C 12Aryl links to each other with the main polymer chain skeleton, and functional group is selected from the combination of halogen, hydroxyl, sulfonate radical, phosphonate radical, nitro, amido, phosphino-, carbonyl, carbamate groups, carboxyl and sulfydryl and multiple these groups.
7, the polymkeric substance of claim 6, wherein polymkeric substance is the Polyglycol 166-450 derivative.
8, the polymkeric substance of claim 7, wherein the molecular-weight average of Polyglycol 166-450 derivative is about 15000 to about 80000 dalton.
9, the polymkeric substance of claim 7, wherein the Polyglycol 166-450 derivative is a Polyglycol 166-450 amine.
10, the polymkeric substance of claim 9, wherein derivative is the Trimethylamine 99 group.
11, the polymkeric substance of claim 9, wherein derivative is the triethylene amine groups.
12, the polymkeric substance of claim 9, wherein derivative is the quadrol group.
13, the polymkeric substance of claim 9, wherein derivative is the diethylenetriamine group.
14, the polymkeric substance of claim 9, wherein derivative is the tetren group.
15, the polymkeric substance of claim 9, wherein derivative is the mixture of two or more amine groups.
16, the polymkeric substance of claim 1, wherein the water-soluble of polymkeric substance is dissolving at least 0.01 gram polymkeric substance in per 1000 ml waters.
17, the polymkeric substance of claim 16, wherein the water-soluble of polymkeric substance is dissolving 1 to 10 gram polymkeric substance in per 1 ml water.
18, contain the polymkeric substance of claim 1 and the oral property pharmaceutical formulation of medicine acceptable carrier.
19, the pharmaceutical formulation of claim 18, wherein polymkeric substance is the Polyglycol 166-450 derivative.
20, a kind of method that reduces phosphonate radical in the animal body or oxalate comprises the pharmaceutical formulation of the claim 18 of taking significant quantity.
21, the method for claim 20, wherein pharmaceutical formulation is the pharmaceutical formulation of claim 19.
22, the method for claim 21, the significant quantity that wherein reduces phosphonate radical are that every meal about 1 is to about 15 grams.
23, the method for claim 21, the significant quantity that wherein reduces oxalate are that every meal about 0.6 is to about 5 grams.
24, the polymkeric substance of claim 1 is as the purposes of the reagent of phosphonate radical or oxalate in the reduction animal body.
25, the preparation method of the polymkeric substance of claim 1 is included under the lewis acidic existence of medium tenacity, in the solvent as chain terminator Epicholorohydrin is not being reacted.
26, the method for claim 25, wherein solvent is a methylene dichloride.
27, the preparation method of the polymkeric substance of claim 1 is included under the lewis acidic existence of medium tenacity, will make 3 in not as the solvent of chain terminator, 4-two chloro-1, and the 2-butylene oxide ring reacts.
28, the preparation method of the defined polymkeric substance of claim 1, wherein used catalyzer is selected from hexafluorophosphoric acid triethyl oxygen, fluoroboric acid, triethyl aluminum and two (trifluoromethanesulfonic acid) 1,2-second diester.
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